Hypoxia is observed in both human and animal models. Pimonidazole hydrochloride, a chemical probe for tissue hypoxia, detected hypoxic regions in human atherosclerotic carotid arteries, yet not in non-diseased aorta (4, 31). The low oxygen level in atherosclerotic plaques exacerbates vascular impairments, as hypoxia-induced angiogenesis from the vasa vasorum supplies oxygen to the plaque (32). Newly developed vessels in the plaque cause destabilization, resulting in enhanced thrombosis and the infiltration of additional immune cells (33, 34). Furthermore, hypoxia stimulates the activation of the inflammasome in macrophages, increasing the secretion of inflammatory cytokines (35). Another report suggested that hypoxic conditions suppress the migration of macrophages in the lesion area, promoting the accumulation of innate immune cells and lipids by disrupting ABCA1 (7, 36). Thus, plaque hypoxia is generally associated with necrotic core expansion due to immune cell exhaustion, reducing efferocytosis (31).

Mechanistically, HIFs orchestrate these dynamic alterations in the lesion microenvironment in response to hypoxia. Figure 1 illustrates the transitions of macrophage subtypes and their major functions in response to changes in the atherogenic microenvironment. Since HIFs are stabilized under low-oxygen conditions, hypoxia in atherosclerotic lesions stabilizes the HIFs in the human and mouse aortas (4, 7). Among many attempts to identify the influence of PHDs on the progression of atherosclerosis (37–41), Van Kuijk et al. utilized three mouse models deficient in PHD1, PHD2, and PHD3 (40). Among these, HIF-1α stabilization was observed in myeloid PHD2-deficient mice, resulting in a remarkable phenotype. According to the results of transcriptomic analysis, the expression of Bnip3 mRNA, which is related with apoptosis, was increased, while collagen content and fibrous cap thickness were significantly elevated (40). These findings suggest that myeloid PHD2 deficiency exacerbates atherosclerosis by stabilizing HIF-1α and promoting plaque fibrosis through macrophage–fibroblast interactions (40). Another experiment reported that an overactive inflammatory response in myeloid cells, particularly macrophages, was induced after bone marrow transplantation or macrophage depletion (41). Since NF-κB and HIF-1α were activated in PHD3-deficient macrophages, M1 polarization and cytokine secretion were increased in vitro (41). These studies suggest that HIFs influence the differentiation of macrophages into M1-like or M2-like phenotypes via biological pathways, and HIFs control the main functions of macrophages, including apoptosis and inflammation. Consistent with these findings, however, it is remains controversial that whole-body PHD3 deficiency in Ldlr KO mice leads to increased plasma lipid levels and hematocrit without altering atherosclerotic plaque size, suggesting that chronic HIF-2α stabilization may induce systemic metabolic disturbances without improving vascular outcomes (42).

Although both HIF-1α and HIF-2α share structural similarities and activate some genes as transcription factors, they also regulate unique genes in different ways. Macrophages exhibit distinct patterns caused by different inflammatory or metabolic responses depending on whether HIF-1α or HIF-2α is involved. It is essential to understand the difference between HIF-1α and HIF-2α in the pathophysiological aspects of HIF-mediated macrophage polarization. Polarization of macrophages promotes the development of two distinct macrophage subtypes: proinflammatory M1-like and anti-inflammatory M2-like macrophages. These different phenotypes exhibit dynamic plasticity in response to various circumstances or stimuli, including hypoxia, metabolic stress, and inflammation (43). Since HIFs are activated under hypoxic conditions, current research is investigating the role of HIF-1α and HIF-2α in the effects on macrophage phenotypes. HIF-1α is related to the M1-like phenotype, which is mostly activated in inflammatory states. HIF-1α upregulates inflammatory cytokines, including TNF-α and IL-6, as well as NOS2 (iNOS) expression, enhancing nitric oxide (NO) production within the cell to protect against pathogens (14). Furthermore, NO generated by HIF-1α sustains the TCA cycle by activating the aspartate–arginosuccinate shunt for inflammation in macrophages (44). M1 polarization is influenced by inflammatory cytokines induced by succinate dehydrogenase breakdown in the TCA cycle (12). These HIF-1α-mediated inflammatory responses in macrophages play a more significant role in acute inflammation due to the increased iNOS expression-mediated clearance of pathogens (13). In chronic inflammatory conditions, however, the direct gene targets of HIF-1α are not yet fully defined, and its role remains to be clarified beyond its acute pro-inflammatory functions.

Conversely, HIF-2α has often been linked with M2 polarization and tissue resolution (45, 46). In many settings, HIF-2α upregulates cytokines and genes related to lipid metabolism and wound healing such as Arg1 (47, 48). Meanwhile, Arg1 is one of representative HIF-2α-dependent genes known as anti-inflammatory marker that associated with lipid metabolism and downregulating pro-inflammatory genes for preventing the exacerbation of atherosclerosis (16, 49). However, HIF-2α is not exclusively anti-inflammatory. Context-dependent evidence shows that HIF-2α can also promote pro-inflammatory responses, for example, by inducing IL-6 in hepatic macrophages (50). Additionally, HIF-2α enhances macrophage infiltration and survival via regulating CSF1R expression that consists chronic inflammation (51, 52). Such findings demonstrate that HIF-2α functions extend beyond the M2 paradigm, with roles in both inflammatory amplification and tissue repair depending on microenvironmental cues.

In hypoxic conditions, the interaction between HIFs affects macrophages by shifting their phenotypic characteristics. This hypoxia-driven mechanism provides important insights into the role of HIFs in diseases such as cancer, chronic inflammation, and ischemic injury (53). Thus, both HIF-1α and HIF-2α act along a continuum: HIF-1α preferentially drives acute inflammatory responses, while HIF-2α more often supports resolution, but both isoforms can contribute to control the inflammation in distinct ways. HIF-2α promotes cell homeostasis by suppressing Marco expression, thereby regulating oxidative stress and efferocytosis in stable macrophages (54). This suggests that HIF-2α regulates the excessive activity of macrophages under normal conditions. Comparatively, HIF-1α can be activated by LPS even under normoxic conditions, strongly enhancing the expression of inflammation-related genes (55). This implies that HIF-1α is crucial in mediating immune responses in response to infected or inflamed macrophages.

Overall, HIF-1α and HIF-2α function through specific pathways to mediate macrophage polarization and regulate macrophage functions. Figure 2 highlights these context-specific and dynamic roles: HIF-1α largely associated with acute inflammatory programs, HIF-2α often linked to resolution, but also capable of contributing to inflammation depending on environmental conditions. Understanding these antagonistic interactions will improve therapeutic strategies targeting HIF-1α and HIF-2α.

HIFs in macrophages have attracted considerable attention in various diseases; HIF-1α is related to M1 polarization, whereas HIF-2α is associated with M2 polarization (14, 56). Inflammatory responses are reduced in HIF-1α-depleted macrophages in atherosclerosis, and the plaque and necrotic core areas are diminished in HIF-1α-deficient mice (40, 57). Previous research using mice suggested that HIF-2α regulates the expression of mitochondrial Cpt1a in macrophages, which inhibits the formation of NLRP3 inflammasome complex to suppress inflammation (58). Since inflammation is a key risk factor for atherosclerosis, it could be assumed that HIF-2α-mediated suppression of inflammation regulates the development of atherosclerosis. However, no clear evidence exists that macrophage HIF-2α reduces atherosclerosis. Therefore, further studies on the regulatory mechanisms through which HIF-2α signaling functions are required to understand the development of atherosclerosis.

An insufficient oxygen supply to tissue leads to cellular stress, which inhibits physiological processes, including the TCA cycle (59). Subsequently, the cells attempt to reprogram their metabolic processes to generate energy and combat the harsh microenvironment. Immune cells, such as macrophages, require more energy for inflammatory responses. Recently, the immune system–metabolism network has been widely studied to identify the interactions between inflammation and metabolism in cells and tissues (60–62). Inflammatory conditions such as tumors and atherosclerosis are associated with metabolic shifts influencing cellular pathology (63, 64). For instance, foamy macrophages in atherosclerotic lesions exhibit enhanced expression of lipid metabolism–related genes and display anti-inflammatory characteristics (21). Recent findings suggest that the pathological milieu of atherosclerotic plaques not only drives foam cell formation but also modulates their inflammatory output. Consequently, researchers are investigating the regulation of inflammation through foam cell-mediated modulation of lipid metabolism (18, 29, 65). Importantly, inflammation in the atherosclerotic plaques is known to be closely associated with hypoxic conditions (66). While HIFs are key transcriptional regulators, the functional role of these transcription factors in lipid metabolism remains controversial. Thus, it is essential to investigate the emerging paradigm in which foam cells, influenced by the dual stressors of hypoxia and lipid overload, play a role in modulating inflammation within lesions. Ultimately, understanding the roles of HIFs in lesion progression or resolution may offer valuable therapeutic insights into atherosclerosis.

Recent comprehensive data revealed that foamy macrophages, which excessively uptake oxLDL, exhibited significantly elevated mRNA expressions of Fabp4, Lgals3, Trem2, Plin2, Lpl, Cd36, and Abca1 (21, 67). These genes are enriched in the PPARγ signaling pathway, which regulate lipid metabolism. Previous research suggests that PPARγ promotes foam cell formation by regulating the expression of Fabp4 and Cd36 in macrophages (28, 68).

HIFs regulate pivotal physiological processes in macrophages under hypoxic conditions. Since HIFs are activated in plaque macrophages in the atheroma of human and mice, several studies have demonstrated the effect of hypoxia on lipid accumulation in macrophages (7, 69). Notably, HIF-1α can regulate lipid metabolism in macrophages by controlling the expression of genes related to lipid metabolism, such as Lpin1 and Abca1, thereby increasing lipid accumulation and exacerbate atherosclerosis (70). Nevertheless, HIF-1α primarily promotes glycolysis in hypoxic conditions by upregulating Glut1, Hk2, and Ldha, which contribute to inflammatory processes and protect against the infections of anaerobic organisms (71, 72).

Lipid uptake by macrophages is increased under hypoxic conditions compared to normoxic conditions; similar results were obtained following oxLDL treatment (7, 73). Thus, HIFs may promote lipid accumulation in macrophages under hypoxic conditions. Notably, the bone marrow-derived macrophages from Hif2a-deficient mice exhibited a shift in lipid metabolic gene expression compared to wild-type controls (45). The expressions of genes involved in fatty acid synthesis (Acaca, Fasn, and Scd1) and lipid storage (Dgat1 and Plin2) were markedly reduced. Conversely, genes associated with β-oxidation (Acox2 and Cpt1a) were significantly upregulated. These data indicate that HIF-2α promotes fatty acid synthesis and storage in macrophages while suppressing fatty acid oxidation, thereby contributing to the lipid-laden phenotype observed in hypoxic lesions.

Lipid accumulation in hepatocytes due to chronic alcohol consumption or genetic mutations, can induce non-alcoholic fatty liver disease (NAFLD) and steatosis, which are commonly associated with tissue hypoxia. In this hypoxic condition, HIF-1α controls glucose metabolism, whereas HIF-2α regulates lipid metabolism (74, 75). Notably, overexpression of HIF-2α levels in hepatocytes exacerbates NAFLD or steatosis by increasing lipid accumulation through enhanced Cd36 expression; however, HIF-1α does not affect Cd36 expression under hypoxic conditions (76).

Although HIF-1α is essential for cellular adaptation to hypoxic conditions and maintaining glucose homeostasis in hepatocytes, it can also induce fibrosis in NAFLD livers by HIF-1α through the PTEN/p65 signaling pathway activation (75, 77). However, whether HIF-1α exacerbates or attenuates liver fibrosis through lipid metabolism regulation remains controversial (78). For example, HIF-1α has been shown to enhance MCP-1 expression and exacerbate alcoholic liver steatosis via lipid accumulation (79). On the contrary, other studies suggest that HIF-1α mediates lipid metabolism through the PPAR-α/ANGPTL4 pathway or Lipin1 expression, which suppresses NAFLD progression (80, 81).

Conversely, somatic mutations in the oxygen-dependent domain (ODD) have been reported to stabilize HIF-2α under normoxic conditions in certain NAFLD patients (82, 83). These patients exhibited increased lipid droplets in hepatocytes, as well as elevated liver weight and body weight, resulting from the gain-of-function mutation. Meanwhile, a HIF-2α mutation in hepatocytes enriches the lipid metabolic pathways, especially in HIF-2α mutant mice fed a high-fat diet; these mice also exhibit increased levels of nuclear HIF-2α and its target perilipin-2 (PLIN2) (84). Furthermore, in intestinal Hif-2α KO mice, the hepatic expression of fatty acid transport and lipogenesis-related genes such as Srebp1c, Cidea, Cd36, Fabp4, Sdc1, and Plin2 was significantly reduced, whereas the expression of β-oxidation-related genes (Acox2, Acsl1, and Acaa1a) was increased (85). These findings highlight the multifaceted roles of HIF-2α in promoting lipid uptake and storage while concurrently suppressing fatty acid catabolism.

Collectively, these studies highlight HIF-2α as a pivotal transcriptional regulator of lipid metabolic programs in hepatocytes. Indeed, HIF-2α plays a significant role in the development and progression of steatosis and fatty liver disease by enhancing lipid accumulation and impairing oxidative lipid clearance. These data provide compelling evidence that HIF-2α is a direct modulator of lipid homeostasis at both cellular and systemic levels.

Most studies on atherosclerosis have traditionally focused on vascular and immune cells; however, recent research has suggested that enterocytes regulate systemic lipid homeostasis and inflammatory responses. Enterocytes exhibit unique metabolic adaptations under chronic low-oxygen conditions, which are closely associated with microbial symbiosis and the maintenance of intestinal function. Intestine is sensitive to oxygen concentrations as a major organ responsible for dietary lipid absorption and ceramide synthesis processes that are precisely controlled by HIF signaling (85). Both HIF-1α and HIF-2α act as the metabolic detectors regulating metabolism in hypoxic enterocytes. In the context, understanding the mechanism of metabolic and inflammatory pathways that are regulated by intestinal HIFs is essential for elucidating how intestinal hypoxia indirectly contributes to the systemic inflammatory milieu of atherosclerosis.

HIF-1α is generally expressed in enterocytes, which promotes glucose uptake and glycolysis by regulating the expression of Glut1 and other glycolysis enzymes (86, 87). GLUT1 transports glucose into cells to increase glucose absorption, thereby activating the PI3K/Akt/mTOR pathways (88). Furthermore, HIF-1α directly interacts with GLUT1 and glycolytic enzymes, including PFKP, to form a glycolytic complex, which promotes glycolysis without transcriptional regulation, ultimately optimizing energy generation through increased lactic acid production (87). An increased lactic acid level helps regulate pH levels in cells, which stimulates the production of occludin to maintain intestinal barrier function (87).

Interestingly, recent research has reported that HIF-2α expression is increased in the ileum of obese patients, whereas HIF-1α levels in biopsies from obese and non-obese patients did not differ (85). According to that, it has been posited that only HIF-2α is upregulated among the HIF family. Additionally, intestinal HIF-2α overexpression through lentivirus–HIF-2α (LV–HIF-2α) transfection into ApoE KO mice increased Lgals3 expression in macrophages and genes related to ceramide synthesis, whereas macrophage Lgals3 expression was reduced in intestine from Hif-2α KO mice (89). Conversely, Hif2a knockout restricted to the intestinal epithelium resulted in reduced LGALS3 expression, reinforcing the regulatory role of intestinal HIF-2α in this axis.

These findings indicate that intestinal HIF-2α influences atherosclerotic lesion biology indirectly by modulating lipid metabolites and inflammatory mediators. By regulating LGALS3 and ceramide-related pathways, intestinal HIF-2α appears to contribute to the systemic inflammatory milieu that drives lesion progression. This data further contributes to the emerging role of HIF-2α as a tissue-specific orchestrator of lipid metabolism and inflammation across multiple organ systems.

Since adipose tissue is metabolically active tissue with both endocrine and immune functions, obesity, a representative disease of adipose tissue, results in chronic inflammation and metabolic dysfunction. Within this diseased microenvironment, HIF signaling regulates lipid metabolism, insulin resistance, and immune activation as a key regulator.

HIF-2α depletion in adipocytes elevates inflammatory responses and enhances insulin resistance, inducing metabolic dysfunction (17). Moreover, HIF-2α regulates Acer2 expression in adipocytes, which contributes to ceramide catabolism, lowering blood ceramide levels and reducing atherosclerotic lesions (17). Alternatively, HIF-1α can negatively exacerbate obesity and insulin resistance by increasing adipose inflammation via the upregulation of inflammatory cytokines and chemokines (90, 91). Moreover, insulin resistance is closely related to HIF-1α, which increases PDK1/2/4 expression, promoting glycolysis metabolism and enhancing lactic acid production (90). Furthermore, both insulin resistance and inflammation are reduced in the adipose tissues of adipocyte-specific Hif-1α-deficient mice fed high-fat diet by activating the glucagon-like peptide-1 (GLP-1) pathway (92). Conversely, adipocyte HIF-1α overexpression promotes obesity and decreases metabolism through suppressing cell respiration in brown adipose tissue (BAT) (93). Additionally, HIF-1α regulates VEGF expression, which promotes angiogenesis in obese mice (94).

These findings highlight the dual immune–metabolic roles of adipose tissue in health and disease, wherein resident macrophage subtypes and hypoxia-responsive pathways interact to regulate lipid flux, inflammatory tone, and ultimately, cardiovascular risk.

The interaction between inflammation and metabolism is a complex but important physiological process. Figure 3 summarizes an overview of HIF activity across major organs involved in physiological processes. In macrophages, inflammation either regulates metabolism or is regulated by the byproducts of metabolism (61, 95). The mechanisms involved in immunometabolism are complex but essential for maintaining cellular homeostasis. The immunometabolic pathways are activated under stressful conditions, such as in tumor microenvironments, where inflammation and tissue hypoxia are commonly induced (96).

Under hypoxic conditions in diseased tissues, HIF-1α activates glycolysis to generate ATP and induces proinflammatory cytokines when mitochondrial respiration is limited (35, 97). Numerous studies suggest that HIF-1α is strongly linked to the progression of atherosclerosis and metabolic disorders (57, 98). As prolonged hypoxia and inflammation become chronic, the pro-inflammatory state gradually shifts toward a lipid-metabolic adaptation as HIF-1α activity declining as HIF-2α progressively increases in a timely manner (13). This sequential activation of HIF isoforms represents a temporal and functional continuum linking the initiation of inflammation to its metabolic resolution.

HIF-2α mediates lipid metabolism and anti-inflammatory responses that promote tissue protection and recovery at the later adaptive phase of hypoxia. Although the HIF-2α-mediated regulation of lipid metabolism has not been as extensively studied as that of HIF-1α, the anti-inflammatory role of HIF-2α is possibly related to the protection or resolution of atherosclerosis. HIF-2α activates fatty acid β-oxidation to expend ATP and suppress inflammation in macrophages; thus, it is possible to ameliorate atherosclerosis (58, 98). Further evidence suggests that macrophage HIF-2α induces arginase 1 and downregulates molecules involved in the harmful effects of atherosclerosis, including NO and pro-inflammatory cytokines (14, 99). Arginase 1 is a representative anti-inflammatory marker regulated by HIF-2α in hypoxic conditions (14, 100). Arginase 1 promotes continuous efferocytosis, which is driven by the metabolism of arginine derived from apoptotic cells in the plaque, a process required for the regression of atherosclerosis (49). Although this clear evidence shows that arginase 1 is involved in resolving atherosclerosis, whether HIF-2α directly affects atherosclerosis remains unproven. However, HIF-2α-mediated regulation of ceramide biology offers mechanistic insight into how hypoxia and lipid metabolism converge to influence disease outcomes in tissues such as the liver, gut, and vasculature (17, 50, 85).

Nevertheless, several studies have reported that HIF-2α activation may exacerbate inflammation and metabolic dysregulation under certain pathological conditions. For example, HIF-2α activation in macrophages enhances IL-6 and TNF-α expression that sustains chronic inflammation in tumor and acute inflammatory models (51). Similarly, endothelial HIF-2α downregulates tissue factor pathway inhibitor (TFPI), thereby increasing pro-thrombotic and pro-inflammatory potential under hypoxic stress (101). These findings suggest that excessive or prolonged HIF-2α activation may contribute to maladaptive inflammatory or metabolic responses depending on the tissue context. This cross-tissue coordination underscores that hypoxia-responsive HIF signaling not only orchestrates macrophage metabolic programming but also integrates systemic immune-metabolic communication across organs.

Together, these mechanisms involving HIF-1α and HIF-2α suggest that HIF-1α predominantly sustains inflammatory glycolytic metabolism during acute hypoxia, whereas HIF-2α restores lipid and redox balance under chronic hypoxia, thereby supporting inflammation resolution and tissue stability. Collectively, the complex paradigms may suggest in this review indicate that the interplay between HIF-1α and HIF-2α defines a temporal and functional axis of macrophage metabolism integrating a unified mechanistic framework that links hypoxia, lipid metabolism, and immune regulation in atherosclerosis in a timely manner.